The theme of my research career has been to understand mechanisms governing the regulation of gene expression in diverse systems through a variety of approaches. Using molecular biology techniques, I investigated the regulation of late gene expression during Epstein Barr virus lytic infection in graduate school. Through biochemical approaches, I have recently been investigating a novel protein-only (prion) mechanism for regulating translation termination fidelity in yeast. The development of severe neurodegenerative disorders in mammals (e.g. Huntington's, Alzheimer's, and the transmissible spongiform encephalopathies) is believed to occur through a related process. With this award, I will broaden my post-doctoral training to genetic and cell biological techniques by extending my in vitro studies to the in vivo system. My goal is to elucidate the molecular mechanism by which eukaroytic release factor 3 is reversibly inactivated as a prion and the regulation of this process. I intend to establish an independent research program at an academic institution to develop a mechanistic understanding of the translation termination process, its regulation, and the consequences of translational ambiguity through multidisciplinary approaches. Accurate termination is essential for faithful protein synthesis, and errors in this system have been linked to nearly 200 genetic disorders. My faculty research will focus on: 1)determining the factors active in and the signals regulating discreet steps in termination, and 2) identifying and characterizing the functions and targets of new and existing modifiers of termination efficiency. It is only through a complete understanding of this process that we can fully appreciate its role in basic cellular physiology and human disease.